Hepatocyte growth factor (hereinafter referred to as HGF) was originally identified as a growth factor for mature hepatocytes, and its gene (cDNA) was cloned in 1989 (see non-patent literatures 1 and 2).
It has been revealed so far that HGF exerts various biological activities such as cell proliferation, promotion of cell migration, morphogenesis induction, cell death inhibition and the like on various cells as well as hepatocytes (see non-patent literatures 3 to 6).
The biological activities of HGF are expressed via its receptor, i.e. c-Met tyrosine kinase. HGF has various biological activities and has functions of repairing and protecting various tissues from various injuries.
Angiogenesis promoting activity is one of HGF functions of regeneration or protection of tissues. HGF not only promotes proliferation and migration of vascular endothelial cells, but also shows in vivo potent angiogenesis-inducing activity (see non-patent literatures 7 to 10).
Further, HGF has an activity of inhibiting cell death of vascular endothelial cells (see non-patent literatures 11 to 13).
Lung is an organ composed of a large number of alveoli. The air taken into the body by respiration is passed through trachea and then enters into bronchi. Bronchi are further branched, and one bronchiole is connected to one alveolus. Human alveolus is a small sac of about 0.2 mm diameter, and is surrounded by capillaries. Gas exchange takes place in the alveoli, i.e., oxygen is taken from the inspired gas entered through the bronchi into the alveoli, and carbon dioxide in the blood is exhausted into the alveoli as expired gas. Pulmonary emphysema is physiologically a progressive destruction of the alveoli, and the surface area of alveoli available for gas exchange is reduced as disease progresses. Inadequate gas exchange in the alveoli causes a shortage of oxygen in the blood. With the progress of the disease, lung elasticity is lowered, resulting in respiratory difficulty. In addition, since adult lung is an organ which cannot spontaneously grow or regenerate itself, pulmonary emphysema is considered to be a progressive and irreversible disease. Massaro et. al reported that treatment with all-trans-retinoic acid (ATRA) anatomically and physiologically regenerated lung in an animal model of pulmonary emphysema (see non-patent literature 14). Further, ATRA is known to activate genes involved in lung development and to promote alveolar septation and growth of lung. However, clinical trials using ATRA failed to show significant improvement in lung structure or lung function in pulmonary emphysema patients (see non-patent literature 15).
It has been reported that HGF promotes the growth of alveolar epithelial type II cells or bronchial epithelial cells, and that HGF is involved in the repair of alveolar epithelial cells (see non-patent literatures 16-19). Also, a study on the effect of HGF on acute lung injury revealed that HGF is newly produced in the lung after injury, and that when HGF is administered to animals with an injured lung, cell proliferation in the lung tissue is stimulated and repair of the injured lung is promoted (see patent literature 2).
However, any of the above-mentioned literatures does not describe that HGF induces differentiation of bone marrow cells into alveolar cells and that regeneration or formation of alveoli is promoted by such differentiation induction.
[Patent literature 1] JP-A-89869/1996
[Patent literature 2] JP-A-172207/1994
[Non-patent literature 1] Biochemical and Biophysical Research Communications, 1984, vol. 122, p. 1450-1459
[Non-patent literature 2] Nature, 1989, vol. 342, p. 440-443
[Non-patent literature 3] The Journal of Cell Biology, 1985, vol. 129, p. 1177-1185
[Non-patent literature 4] The Journal of Biochemistry, 1986, vol. 119, p. 591-600
[Non-patent literature 5] International Review of Cytology), 1999, vol. 186, p. 225-260
[Non-patent literature 6] Kidney International, 2001, vol. 59, p. 2023-2038
[Non-patent literature 7] The Journal of Cell Biology, 1992, vol. 119, p. 629-641
[Non-patent literature 8] Proceedings of the National Academy of Sciences of the United States of America, 1993, vol. 90, p. 1937-1941
[Non-patent literature 9] Circulation, 1998, vol. 97, p. 381-390
[Non-patent literature 10] Hypertension, 1999, vol. 33, p. 1379-1384
[Non-patent literature 11] Journal of Hypertension, 2000, vol. 18, p. 1411-1420
[Non-patent literature 12] Hypertension, 2001, vol. 37, p. 581-586
[Non-patent literature 13] Diabetes, 2002, vol. 51, p. 2604-2611
[Non-patent literature 14] Massaro, G. D., et. al, Nature Medicine, 1997, vol. 3, p. 675-677
[Non-patent literature 15] Mao, J. T., et. al, American Journal of Respiratory & Critical Care Medicine, 2002, vol. 165, p. 718-723
[Non-patent literature 16] Mason R J, et. al, American Journal of Respiratory Cell and Molecular Biology, 1994, vol. 11, p. 561-567
[Non-patent literature 17] Shiratori M, et. al, American Journal of Respiratory Cell and Molecular Biology, 1995, vol. 12, p. 171-180
[Non-patent literature 18] Ohmichi H, et. al, The American Journal of Physiology, 1996, vol. 270, p. L1031-L1039
[Non-patent literature 19] Sakamaki, Y, et. al, American Journal of Respiratory Cell and Molecular Biology, 2002, vol. 26, p. 525-533.